4.4 Article

Adenine Induces Differentiation of Rat Hepatic Stellate Cells

Journal

DIGESTIVE DISEASES AND SCIENCES
Volume 57, Issue 9, Pages 2371-2378

Publisher

SPRINGER
DOI: 10.1007/s10620-012-2183-7

Keywords

Adenine; Stellate cells; Chemotaxis; Differentiation

Funding

  1. NIH [R01DK076674-01A2]
  2. VA Merit Award

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Adenine is a uric acid pathway metabolite of no known function, and has recently been identified as a ligand for a rat G protein-coupled receptor. Due to the known role of other uric acid pathway metabolites in HSC biology, we tested the ability of adenine to induce HSC differentiation. RT-PCR was performed for adenine receptor expression in T-6 and primary rat HSC. T-6 and primary rats HSC were cultured with and without adenine, and stellation examined. Next, we examined inhibition of calcium signaling using caged IP3. To test if adenine inhibits HSC chemotaxis T-6 cells and rat HSCs were cultured with or without adenine for 24 h in a transwell assay with PDGF as the chemoattractant. cDNA was prepared from T-6 and primary HSC for quantification of collagen 1 mRNA using real-time PCR. We found that mRNA for the adenine receptor is expressed in T-6 cells and primary rat HSC. Also, adenine induces HSC stellation and adenine inhibits IP3 mediated increase in cytosolic [Ca2+](i) and inhibits chemotaxis in T-6 cells and primary rat HSC. Adenine was also shown to up-regulate alpha-SMA and collagen 1, and this effect is lost by using specific si-RNA for the adenine receptor. Finally, adenine inhibits endothelin-1-induced gel contraction. The adenine receptor is present in T-6 cells and primary rats HSC. Adenine, via the adenine receptor, induces morphological change, and cytosolic calcium signaling, inhibits chemotaxis, and up-regulates collagen 1 mRNA in HSCs.

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